The broad and long-term objective of this research project is to develop mechanism-based therapies for paroxysmal atrial tachyarrhythmias including paroxysmal atrial fibrillation (PAF) and paroxysmal atrial tachycardia (PAT) in canine models. It is known that the autonomic nervous system (ANS) is important in controlling both heart rhythm and cardiac contractility. In the previous funding period, we successfully developed methods to record autonomic nerve activities in ambulatory dogs, and documented their importance in cardiac arrhythmogenesis in dogs with pacing-induced heart failure and intermittent rapid atrial pacing. We also for the first time developed methods to record intrinsic cardiac nerve activity (ICNA) to document its importance in triggering AF of ambulatory dogs. However, more studies need to be done before we can translate these new findings to patient care. We propose to pursue the following specific aims in the next funding period: Aim 1: Effects of GP ablation on AF. We will record bilateral stellate ganglion nerve activity (SGNA) and vagal nerve activity in dogs with and without cryoablation of superior left GP (SLGP) and ligament of Marshall (LOM) GPs in the heart. The results will be used to test the hypotheses that (1) GP ablation prevents spontaneous PAT and PAFs in ambulatory dogs and (2) The antiarrhythmic effects of GP ablation depends at least in part on successful reduction of coordinated firing between ECNA and ICNA. Aim 2: Effects of low-level vagus nerve stimulation (LL-VNS) on cardiac nerve activity and spontaneous atrial tachyarrhythmias. We will simultaneously measure left stellate ganglion nerve activity (SGNA) and superior left GP nerve activity (SLGPNA) while performing either LL-VNS or sham VNS in ambulatory dogs. The nerve recordings and histological findings will be used to test the hypothesis that (1) LL-VNS results in reduced SGNA, accompanied by structural neural remodeling in the left stellate ganglion and (2) LL-VNS can reduce the incidence of PAT and PAF in dogs with intermittent rapid atrial pacing. Aim 3: Effects of VNS on atrioventricular (AV) conduction during sustained AF. We will perform a study to test the hypothesis that left VNS can modulate AV node conduction through the activation of the inferior vena cava-inferior atrial GP (IVC- IAGP) during sustained AF, and that VNS can improve ventricular rate control by simultaneously reducing the SGNA and increasing IVC-IAGPNA. Aim 4: Differential extrinsic cardiac nerve activity (ECNA) and ICNA remodeling in heart failure. We will perform simultaneous SGNA, ligament of Marshall nerve activity (LOMNA) and left ventricular (LV) pressure recordings at baseline and during pacing-induced heart failure to test the hypotheses that (1) LOMNA directly control LV contractility at baseline, (2) Heart failure increases SGNA but reduces LOMNA, leading to ineffective neural control of LV contraction. (3) SGNA, not LOMNA, is responsible for atrial tachyarrhythmias in heart failure. All four aims have significant clinical relevance, and may lead to novel therapeutic approaches to controlling AF and heart failure. PUBLIC HEALTH RELEVANCE: Atrial fibrillation is the most common arrhythmia in the United States and other developed countries. This research project is relevant to public health because it proposes to investigate the neural mechanisms of atrial fibrillation and to develop mechanism-based therapy of this important cardiac arrhythmia.